人们知道，CD4+ helper T-细胞（重要免疫调控因子）会被HIV-1感染清除，但该病毒是怎样引起细胞死亡的却一直不清楚。在这项研究中，Gary Nabel及其同事发现，HIV-1结合是触发CD4+ T-细胞死亡的必要和充分条件，其结合通过“DNA-依赖性蛋白激酶” (DNA-PK) （DNA修复机制的一部分）的激发以及p53的磷酸化来触发细胞死亡。
这项工作也许可帮助解释病毒库在被HIV感染的患者身上是怎样建立的，并且也表明：用“整合酶”或DNA-PK抑制药物来治疗也许能延长CD4细胞的存活时间和延迟艾滋病的发展。（生物谷Bioon.com）
生物谷推荐英文摘要:
Nature doi:10.1038/nature12274
HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration
Arik Cooper,Mayra García,Constantinos Petrovas,Takuya Yamamoto,Richard A. Koup & Gary J. Nabel
Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4+ T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4+ T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4+ T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.
